Composition for transmucosal adminstration containing conenzyme q as the active ingredient

ABSTRACT

The present invention relates to the supply of coenzyme Q which is highly useful in maintaining human health, and provides a method and preparations whereby coenzyme Q can be efficiently supplied to patients having difficulties in oral administration, aged having swallowing difficulties and patients with diseases caused by topical disorders. It is found that the coenzyme Q concentration in the blood or topical mucosae can be elevated by using a composition for transmucosal administration containing oxidized coenzyme Q and/or reduced coenzyme Q as the active ingredient, wherein the total content of the oxidized coenzyme Q and the reduced coenzyme Q amounts to 0.0001 to 99% by weight of the whole composition.

TECHNICAL FIELD

[0001] The present invention relates to a composition for transmucosaladministration containing coenzyme Q as an active ingredient.

BACKGROUND ART

[0002] Coenzyme Q is an essential component which is distributed in awide variety of living organisms ranging from bacteria to mammals. It isknown that coenzyme Q undergoes oxidation/reduction cycles in livingorganisms and functions as an electron carrier in an electron transportsystem, and reduced coenzyme Q is an antioxidant. It is also known thatin many animals including humans, fishes, and birds, coenzyme Q ismainly composed of coenzyme Q₁₀ having 10 repeat structures in its sidechain, and about 40% to 90% of coenzyme Q present in living organisms isgenerally in its reduced form. Since coenzyme Q can be synthesized inliving organisms, coenzyme Q does not belong to the vitamin group, butit is thought to be substantially the same as vitamins. Also, the humanability of biosynthesis of coenzyme Q₁₀ decreases with aging to decreasethe coenzyme Q₁₀ content in living organisms, and thus the need forsupplying coenzyme Q₁₀ in some form is demanded.

[0003] In coenzyme Q₁₀ oxidized coenzyme Q₁₀ is used as an agent for acongestive heart failure in medical applications. In addition to medicalapplications, oxidized coenzyme Q₁₀ is used as a nutritional supplementor nutritional adjuvant like vitamins, or used for effectively treatingan allergic disease or increasing athletic ability. Therefore, theeffectiveness of oxidized coenzyme Q₁₀ has been reported in a widevariety of fields. Furthermore, the effectiveness for brain diseasessuch as dementia, and the like has been reported, and it can thus beexpected that oxidized coenzyme Q₁₀ has high effectiveness for elderlypersons.

[0004] In this way, coenzyme Q₁₀ has high usefulness, and no toxicity isobserved in a safety test using animals, in which coenzyme Q₁₀ iscontinuously administered to rats for 52 weeks with a high dose of 1.2g/kg/day. Therefore, the coenzyme Q₁₀ is a compound proved to have highsafety (J. Agric. Food Chem., 1999, Vol. 47, P3756-3763). However,coenzyme Q₁₀ is only actually used as a skin agent other than oraladministration, and thus has difficulties in practical administration toa patient with a serious disease, an elderly person or a young child whocannot easily orally intake coenzyme Q₁₀. Furthermore, in a topical sitesuch as the intestinal canal, the nose, or the ears, which are easilyaffected by an allergic disease, a sufficient concentration of coenzymeQ cannot be obtained by oral administration. Therefore, in fact,coenzyme Q cannot be effectively utilized.

SUMMARY OF THE INVENTION

[0005] An object of the present invention is to provide a preparationwhich contains coenzyme Q as an active ingredient, and which can beeasily used for a patient or elderly person having difficulties in oraladministration, or which can effectively supply coenzyme Q to a topicalsite where a sufficient concentration of coenzyme Q cannot be easilyobtained.

[0006] As a result of studies for solving the above problem, theinventors found that coenzyme Q can be absorbed into the body throughmucosal absorption. It was also found that by using a compositioncontaining reduced coenzyme Q, a high blood concentration of coenzyme Qcan be obtained by a preparation of coenzyme Q, as compared with acomposition containing only oxidized coenzyme Q. It was further foundthat coenzyme Q can be effectively transferred to a topical site throughmucosal absorption.

[0007] A composition for transmucosal administration of the presentinvention comprises, as an active ingredient, oxidized coenzyme Qrepresented by formula (1) and/or reduced coenzyme Q represented forformula (2):

[0008] (wherein n represents an integer of 1 to 12)

[0009] (wherein n represents an integer of 1 to 12),

[0010] wherein the total content of oxidized coenzyme Q and reducedcoenzyme Q is 0.0001 to 99% by weight of the whole of the composition.The composition may be applied to humans or animals. Examples of animalsinclude pet animals such as dogs, cats, and the like, race horses,domestic animals such as cows, horses, pigs, rabbits, rats, mice, andthe like, birds, and the like.

[0011] In the present invention, a “composition for transmucosaladministration” means a composition produced in a form to be absorbedinto the body through the mucosae. In the present invention, “themucosae” includes the intestine, the nasal mucosa, the oral mucosa, theotic mucosa, the vaginal mucosa, and the like.

[0012] The present invention provides the composition for transmucosaladministration applied to humans or animals, and thus the presentinvention also provides a method for transferring coenzyme Q into thebody. Furthermore, the present invention provides the composition fortransmucosal administration applied to the mucosae of humans or animalshaving diseases, and thus provides a method for treating diseases. Asconditions for applications, generally known conditions can be usedaccording to the form of the composition used. For example, in the caseof a suppository, a suppository containing coenzyme Q is preferably usedonce a day. In this case, the content of coenzyme Q is preferably 30 mgto 100 mg, and more preferably 50 mg to 100 mg. In the case of eye dropsor nose drops, eye drops or nose drops containing coenzyme Q arepreferably 2 or 3 times a day. In this case, the content of coenzyme Qis preferably 0.01% by weight to 10% by weight, and more preferably 0.1%by weight to 3% by weight.

DETAILED DISCLOSURE OF INVENTION

[0013] The present invention will be described in detail below.

[0014] A compound represented by the above formula (1) is oxidizedcoenzyme Q, and a compound represented by the above formula (2) isreduced coenzyme Q.

[0015] The method for obtaining oxidized coenzyme Q and reduced coenzymeQ is not limited, and for example, a method comprising obtainingcoenzyme Q by a conventional known process such as synthesis,fermentation, extraction from a natural source, or the like, and thenconcentrating each fraction from a chromatography eluate can be used. Inorder to obtain reduced coenzyme Q, if required, a general reducingagent such as sodium borohydride, sodium dithionite (sodiumhydrosulfite), or the like may be added to the coenzyme Q, for reducingoxidized coenzyme Q contained in coenzyme Q to reduced coenzyme Q by aconventional process, and then the obtained reduced coenzyme Q may beconcentrated by chromatography. Reduced coenzyme Q can also be obtainedby applying a reducing agent to existing oxidized coenzyme Q.

[0016] As the oxidized coenzyme Q and reduced coenzyme Q used in thepresent invention, as shown in formulae (1) and (2), a coenzyme having 1to 12 side chain repeat units (n in each formula) can be used.Particularly, a coenzyme having 10 side chain repeat units, i.e.,oxidized coenzyme Q₁₀ and reduced coenzyme Q₁₀, can be preferably used.

[0017] Although the content of coenzyme Q in the composition of thepresent invention is appropriately determined by the application anddosage form, the lower limit of the total content (the content ofoxidized coenzyme Q of the whole of the composition when the compositioncontains only oxidized coenzyme Q, and the content of reduced coenzyme Qof the whole of the composition when the composition contains onlyreduced coenzyme Q) of the oxidized coenzyme Q and the reduced coenzymeQ is 0.0001% by weight of the whole of the composition, and the upperlimit is 99% by weight. Preferably, the lower limit is 0.005% by weight,and the upper limit is 50% by weight. More preferably, the lower limitis 0.01% by weight, and the upper limit is 30% by weight.

[0018] When the composition of the present invention contains bothoxidized coenzyme Q and reduced coenzyme Q, the content of reducedcoenzyme Q of the whole of oxidized coenzyme Q and reduced coenzyme Qpreferably exceeds 20% by weight, and is more preferably 40% by weightor more. The upper limit of the content may be 100% by weight or less,preferably less than 100% by weight, and more preferably 98% by weightor less.

[0019] The composition for transmucosal administration of the presentinvention can be prepared in formulations such as a suppository, avaginal suppository, nose drops, ear drops, an oral mucosal applicator,toothpaste, a troche, a drop, an electuary, an oral solubilizer, and thelike according to the administration route. Each of these formulationscan be produced by a conventional known formulation method usingformulation additives generally used for the formulation.

[0020] In the case of a suppository formulation, examples of formulationadditives include semi-synthetic hardened oils such as Isocacao(produced by Kao Corporation), Witepsol (produced by Huls Corp.),Suppocire (Gattefosse Corp.), Pharmasol (produced by NOF Corporation),Massa Estarinum (produced by Huls Corp.), Novata (produced by HenkelCorp.), a SB base (produced by Taiyo Oil K. K.), and the like; naturalfats and oils such as cacao butter, palm butter, palm seed oil, palmoil, fractional coconut oil, lard, and the like; waxes such as lanoline,reduced lanoline, and the like; hydrocarbons such as vaseline, squalene,squalane, liquid paraffin, and the like; higher alcohols such as laurylalcohol, cetanol, stearyl alcohol, and the like; fatty acid esters suchas butyl stearate, dilauryl malonate, and the like; glycerinmedium-chain carboxylic acid esters such as triolein, tristealin, andthe like; glycerin-substituted carboxylic acid esters such as glycerinacetoacetic ester, and the like; polyethylene glycol and derivativesthereof such as macrogol, acetomacrogol, and the like.

[0021] In the case of nose drops formulation, examples of formulationadditives include physiological saline; buffers such as a lactatebuffer, an acetate buffer, a phosphate buffer, and the like;bactericidal and antiseptic agents such as paraoxybenzoic acid esters,propylene glycol, benzetonium chloride, benzalkonium chloride, sorbicacid or its salts, chlorobutanol, and the like; thickening agents suchas polyvinyl alcohol, polyvinylpyrrolidone, dextran, alginic acid metalsalts, saccharose, gelatin, methyl cellulose, hyaluronic acid metalsalts, and the like; bases for powder administration such as crystallinecellulose, α-cellulose, sodium crosslinked-carboxymethyl cellulose,hydroxypropyl cellulose, β-cyclodextrin, dimethyl-β-cyclodextrin,lactose, and the like.

[0022] The composition of the present invention may further contain anabsorption promoter suitable for each of the dosage forms and purposes.

[0023] The composition for transmucosal administration of the presentinvention can be used for medical products. In this case, examples ofdiseases to be treated include hemorrhoid, idiopathic ulcerativecolitis, a Crohn's disease, a heart failure, cerebropathy, cerebralinfarction, diabetes, diabetic retinopathy, cardiac infarction, allergicrhinitis, pollinosis, conjunctivitis, gingivitis, alveolar pyorrhea, andthe like. In this case, the composition may further contain medicalcomponents other than coenzyme Q.

[0024] In the present invention, a suppository may contain a druggenerally used for an intestinal disease such as hemorrhoid, idiopathiculcerative colitis, a Crohn's disease, or the like; or a substance usedfor the whole body, such as an antipyretic analgesic, a nutritionaladjuvant, or the like.

[0025] In the present invention, nose drops may contain a drug generallyused for allergic rhinitis or pollinosis.

[0026] In the present invention, toothpaste may contain a drug generallyused for gingivitis or alveolar pyorrhea.

[0027] The composition for transmucosal administration of the presentinvention can also be used for alimentation. In this case, thecomposition may further contain a nutritional adjuvant. Examples of thenutritional adjuvant include vitamins, crude drug extracts, herbextracts, polyphenols, propolis, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

[0028] Although the present invention will be described in furtherdetail below with reference to examples and formulation examples, thepresent invention is not limited to these examples.

EXAMPLE 1

[0029] (1) Preparation of Specimen Sample 1

[0030] 1 g of oxidized coenzyme Q₁₀ was melted on a water bath at 50°C., and then macrogol 1000 (PEG 1000) was added to form 10 ml ofmixture. The resultant mixture was homogeneously melt-mixed at 50° C.,and then solidified at room temperature to form a cylindricalsuppository having a diameter of about 5 mm.

[0031] (2) Preparation of Specimen Sample 2

[0032] 1 g of reduced coenzyme Q₁₀ (containing 5% of oxidized coenzymeQ₁₀) was melted on a water bath at 50° C., and then macrogol 1000 (PEG1000) melted by the same method was added to form 10 ml of mixture. Theresultant mixture was homogenously melt-mixed at 50° C., and thensolidified at room temperature to form a suppository. The content ofreduced coenzyme Q₁₀ in the suppository was 95% of the whole of thecoenzyme Q₁₀ and oxidation was not observed during preparation.

[0033] (3) Test of Transmucosal Absorption

[0034] Each of specimen samples 1 and 2 was used as a test sample. Thetest was performed by using male Wistar rats (body weight 250 to 300 g)fasted for one night. Test specimen 1 or 2 was inserted into theintestinum rectum of each rat with a dose of 1 g/kg. After insertion,the blood was collected with time to determine the amount of coenzymeQ₁₀ in the blood plasma. The amount of the coenzyme Q₁₀ in the bloodplasma is shown in Table 1. Each of values is average+standard deviationwith n=10. TABLE 1 Amount of coenzyme Q₁₀ in blood plasma (ng/ml)Suppository containing Suppository containing Time oxidized coenzyme Q₁₀reduced coenzyme Q₁₀ 0 12.88 ± 1.94 (100) 13.79 ± 1.34 (100) 1 11.67 ±2.33 (91) 14.86 ± 1.89 (108) 2 18.51 ± 4.56 (144*) 17.68 ± 3.55 (128) 415.96 ± 3.61 (124) 21.55 ± 4.61 (156*) 8 15.63 ± 3.30 (121) 37.61 ± 4.88(272***) 12 14.75 ± 2.99 (115) 46.11 ± 6.09 (334***) 24 11.37 ± 1.87(88) 28.64 ± 5.50 (207***)

[0035] As described above, it was found that the amount of coenzyme Q₁₀in the blood plasma can be increased by transmucosal administration ofcoenzyme Q₁₀ used as a suppository. This result indicates that coenzymeQ₁₀ which can be only orally administered because of its insolubilitycan be supplied by transmucosal administration even when oraladministration is difficult. It is further surprising that the amount ofcoenzyme Q₁₀ in the blood plasma can be more increased by a suppositorycomprising coenzyme Q₁₀ containing 95% of reduced coenzyme Q₁₀, ascompared with coenzyme Q₁₀ containing 100% of oxidized coenzyme Q₁₀. Itis thus found that the suppository comprising coenzyme Q₁₀ containing95% of reduced coenzyme Q₁₀ is excellent in supplying coenzyme Q₁₀ toliving organisms.

EXAMPLE 2 Test of Mucosal Transition Ability

[0036] Suppositories containing oxidized and reduced coenzyme Q₁₀,respectively, were prepared by the same method as in Example 1. Thetransition ability of coenzyme Q₁₀ to the colic mucosa of a rat wasevaluated by using each suppository. In the test, specimen sample 1 or 2was inserted into the colon of each of male Wistar rats with a dosage of1 g/kg in the same manner as in Example 1. After insertion, the colonwas collected from each rat with time and then sufficiently washed todetermine the amount of coenzyme Q₁₀ in the colic tissue by highperformance liquid chromatography (HPLC). The amount of coenzyme Q₁₀ inthe colic tissue is shown in Table 2. Each of values is average+standarddeviation with n=5. TABLE 2 Amount of coenzyme Q₁₀ in colon (μg/g)Suppository containing Suppository containing Time oxidized coenzyme Q₁₀reduced coenzyme Q₁₀ 0 0.88 ± 0.21 (100) 0.73 ± 0.15 (100) 2 1.22 ± 0.31(138) 1.78 ± 0.56 (243*) 4 1.41 ± 0.48 (160) 2.37 ± 0.62 (325**) 8 1.29± 0.32 (147) 2.19 ± 0.53 (300**) 24 1.07 ± 0.31 (122) 1.64 ± 0.41 (224*)

[0037] As described above, it was found that the amount of coenzyme Q₁₀in the colic mucosa can be increased by transmucosal administration ofcoenzyme Q₁₀ used as a suppository. This result indicates that coenzymeQ₁₀ can be effectively supplied to the mucosa. It is further surprisingthat the amount of coenzyme Q₁₀ in the mucosa can be more increased by asuppository comprising coenzyme Q₁₀ containing 95% of reduced coenzymeQ₁₀, as compared with coenzyme Q₁₀ containing 100% of oxidized coenzymeQ₁₀. It is thus found that the suppository comprising coenzyme Q₁₀containing 95% of reduced coenzyme Q₁₀ is excellent in supplyingcoenzyme Q₁₀ to the mucosae.

PREPARATION EXAMPLE 1 Suppository

[0038] Coenzyme Q₁₀  1.0 g Macrogol  100 g in total

[0039] However, coenzyme Q₁₀ has a reduced form/oxidized form ratio of98:2.

PREPARATION EXAMPLE 2 Eye Drops

[0040] Coenzyme Q₁₀ 0.1 g Glycerin 1.0 g Propylene glycol 1.0 gPolysolvate 80 1.5 g Sodium dihydrogen phosphate 0.1 g Benzalkoniumchloride 0.005 g Distilled water 100 mL in total

[0041] However, coenzyme Q₁₀ has a reduced form/oxidized form ratio of98:2.

INDUSTRIAL APPLICABILITY

[0042] The composition of the present invention has the above-describedconstitution, and is thus excellent in supplying coenzyme Q to the wholebody by a method other than oral administration, and in accumulatingcoenzyme Q in the topical mucosae. Therefore, the composition exhibitsexcellent effects on health care of aged persons or patients withserious diseases, and on diseases occurring in the topical mucosae, suchas an allergic disease and the like.

1. A composition for transmucosal administration comprising, as anactive ingredient, oxidized coenzyme Q represented by formula (1) and/orreduced coenzyme Q represented for formula (2):

(wherein n represents an integer of 1 to 12)

(wherein n represents an integer of 1 to 12), wherein the total contentof oxidized coenzyme q and reduced coenzyme q is 0.0001 to 99% by weightof the whole of the composition.
 2. A composition for transmucosaladministration according to claim 1, wherein the oxidized coenzyme Qrepresented by formula (1) is oxidized coenzyme Q₁₀, and the reducedcoenzyme Q represented by formula (2) is reduced coenzyme Q₁₀.
 3. Acomposition for transmucosal administration according to claim 1 or 2,wherein the composition used as a suppository, nose drops, ear drops, anoral mucosal applicator, a troche, a drop, an electuary, an oralsolubilizer, a vaginal suppository, or a toothpaste.
 4. A compositionfor transmucosal administration according to any one of claims 1 to 3,wherein the composition is used as a medicine.
 5. A composition fortransmucosal administration according to claim 4, further comprising amedicinal ingredient other than oxidized coenzyme Q represented byformula (1) and reduced coenzyme Q represented by formula (2).
 6. Acomposition for transmucosal administration according to claim 4,wherein the composition is used for treating hemorrhoid or an intestinaldisease.
 7. A composition for transmucosal administration according toclaim 6, further comprising a medicine for treating hemorrhoid or anintestinal disease.
 8. A composition for transmucosal administrationaccording to claim 6, wherein the intestinal disease is idiopathiculcerative colitis or a Crohn's disease.
 9. A composition fortransmucosal administration according to claim 4, wherein thecomposition is used for treating a heart failure, cerebropathy, cerebralinfarction, diabetes, diabetic retinopathy, cardiac infarction, allergicrhinitis, pollinosis, conjunctivitis, gingivitis, or alveolar pyorrhea.10. A composition for transmucosal administration according to claim 9,further comprising a medicine for treating a heart failure,cerebropathy, cerebral infarction, diabetes, diabetic retinopathy,cardiac infarction, allergic rhinitis, pollinosis, conjunctivitis,gingivitis, or alveolar pyorrhea.
 11. A composition for transmucosaladministration according to any one of claims 1 to 3, wherein thecomposition is used for alimentation.
 12. A composition for transmucosaladministration according to claim 11, further comprising a nutritionalauxiliary other than oxidized coenzyme Q represented by formula (1) andreduced coenzyme Q represented by formula (2).
 13. A composition fortransmucosal administration according to any one of claims 1 to 12,wherein the composition is applied to a human.
 14. A composition fortransmucosal administration according to any one of claims 1 to 12,wherein the composition is applied to an animal.
 15. A composition fortransmucosal administration according to claim 14, wherein thecomposition is applied to a dog and/or cat.
 16. A composition fortransmucosal administration according to claim 14, wherein thecomposition is applied to a racehorse.
 17. A method for transferringcoenzyme Q into a living organism comprising applying a composition fortransmucosal administration according to any one of claims 1 to 15 tothe human or animal mucosa.
 18. A method for treating a diseasecomprising applying a composition for transmucosal administrationaccording to claim 4 to the human or animal mucosa with a disease.